tbuckley/cabot-search huggingface dataset:
Dynamics and durability of HIV-1 neutralization are determined by viral replication
Authors: Philipp Schommers, Dae Sung Kim, Maike Schlotz, Christoph Kreer, Ralf Eggeling, Anna Hake, Melanie Stecher, Juyeon Park, Caelan E Radford, Adam S Dingens, Meryem S Ercanoglu, Henning Gruell, Stanley Odidika, Marten Dahlhaus, Lutz Gieselmann, Elvin Ahmadov, Rene Y Lawong, Eva Heger, Elena Knops, Christoph Wyen, Tim Kümmerle, Katja Römer, Stefan Scholten, Timo Wolf, Christoph Stephan, Isabelle Suárez, Nagarajan Raju, Anurag Adhikari, Stefan Esser, Hendrik Streeck, Ralf Duerr, Aubin J Nanfack, Susan Zolla-Pazner, Christof Geldmacher, Otto Geisenberger, Arne Kroidl, Wiston William, Lucas Maganga, Nyanda Elias Ntinginya, Ivelin S Georgiev, Jörg J Vehreschild, Michael Hoelscher, Gerd Fätkenheuer, Jason J Lavinder, Jesse D Bloom, Michael S Seaman, Clara Lehmann, Nico Pfeifer, George Georgiou, Florian Klein
Journal: Nature Medicine (2023)

Abstract Human immunodeficiency virus type 1 (HIV-1)-neutralizing antibodies (nAbs) that prevent infection are the main goal of HIV vaccine discovery. But as no nAb-eliciting vaccines are yet available, only data from HIV-1 neutralizers—persons with HIV-1 who naturally develop broad and potent nAbs—can inform about the dynamics and durability of nAb responses in humans, knowledge which is crucial for the design of future HIV-1 vaccine regimens. To address this, we assessed HIV-1-neutralizing immunoglobulin G (IgG) from 2,354 persons with HIV-1 on or off antiretroviral therapy (ART). Infection with non-clade B viruses, CD4 + T cell counts &lt;200 µl −1 , being off ART and a longer time off ART were independent predictors of a more potent and broad neutralization. In longitudinal analyses, we found nAb half-lives of 9.3 and 16.9 years in individuals with no- or low-level viremia, respectively, and 4.0 years in persons who newly initiated ART. Finally, in a potent HIV-1 neutralizer, we identified lower fractions of serum nAbs and of nAb-encoding memory B cells after ART initiation, suggesting that a decreasing neutralizing serum activity after antigen withdrawal is due to lower levels of nAbs. These results collectively show that HIV-1-neutralizing responses can persist for several years, even at low antigen levels, suggesting that an HIV-1 vaccine may elicit a durable nAb response.
Model-based predictions of protective HIV pre-exposure prophylaxis adherence levels in cisgender women
Authors: Lanxin Zhang, Sara Iannuzzi, Ayyappa Chaturvedula, Elizabeth Irungu, Jessica E. Haberer, Craig W. Hendrix, Max von Kleist
Journal: Nature Medicine (2023)

Abstract Most human immunodeficiency virus (HIV) infections occur in cisgender women in resource-limited settings. In women, self-protection with emtricitabine/tenofovir disoproxil fumarate pre-exposure prophylaxis (FTC/TDF-PrEP) constitutes a major pillar of HIV prevention. However, clinical trials in women had inconsistent outcomes, sparking uncertainty about adherence requirements and reluctance in evaluating on-demand regimens. We analyzed data from published FTC/TDF-PrEP trials to establish efficacy ranges in cisgender women. In a ‘bottom-up’ approach, we modeled hypotheses in the context of risk-group-specific, adherence–efficacy profiles and challenged those hypotheses with clinical data. We found that different clinical outcomes were related to the proportion of women taking the product, allowing coherent interpretation of the data. Our analysis showed that 90% protection was achieved when women took some product. We found that hypotheses of putative male/female differences were either not impactful or statistically inconsistent with clinical data. We propose that differing clinical outcomes could arise from pill-taking behavior rather than biological factors driving specific adherence requirements in cisgender women.
Viral and host mediators of non-suppressible HIV-1 viremia
Authors: Abbas Mohammadi, Behzad Etemad, Xin Zhang, Yijia Li, Gregory J Bedwell, Radwa Sharaf, Autumn Kittilson, Meghan Melberg, Charles R Crain, Anna K Traunbauer, Colline Wong, Jesse Fajnzylber, Daniel P Worrall, Alex Rosenthal, Hannah Jordan, Nikolaus Jilg, Clarety Kaseke, Francoise Giguel, Xiaodong Lian, Rinki Deo, Elisabeth Gillespie, Rida Chishti, Sara Abrha, Taylor Adams, Abigail Siagian, Dominic Dorazio, Peter L Anderson, Steven G Deeks, Michael M Lederman, Sigal Yawetz, Daniel R Kuritzkes, Mathias D Lichterfeld, Scott Sieg, Athe Tsibris, Mary Carrington, Zabrina L Brumme, Jose R Castillo-Mancilla, Alan N Engelman, Gaurav D Gaiha, Jonathan Z Li
Journal: Nature Medicine (2023)

Abstract Non-suppressible HIV-1 viremia (NSV) is defined as persistent low-level viremia on antiretroviral therapy (ART) without evidence of ART non-adherence or significant drug resistance. Unraveling the mechanisms behind NSV would broaden our understanding of HIV-1 persistence. Here we analyzed plasma virus sequences in eight ART-treated individuals with NSV (88% male) and show that they are composed of large clones without evidence of viral evolution over time in those with longitudinal samples. We defined proviruses that match plasma HIV-1 RNA sequences as ‘producer proviruses’, and those that did not as ‘non-producer proviruses’. Non-suppressible viremia arose from expanded clones of producer proviruses that were significantly larger than the genome-intact proviral reservoir of ART-suppressed individuals. Integration sites of producer proviruses were enriched in proximity to the activating H3K36me3 epigenetic mark. CD4 + T cells from participants with NSV demonstrated upregulation of anti-apoptotic genes and downregulation of pro-apoptotic and type I/II interferon-related pathways. Furthermore, participants with NSV showed significantly lower HIV-specific CD8 + T cell responses compared with untreated viremic controllers with similar viral loads. We identified potential critical host and viral mediators of NSV that may represent targets to disrupt HIV-1 persistence.
Meta-reinforcement learning via orbitofrontal cortex
Authors: Ryoma Hattori, Nathan G Hedrick, Anant Jain, Shuqi Chen, Hanjia You, Mariko Hattori, Jun-Hyeok Choi, Byung Kook Lim, Ryohei Yasuda, Takaki Komiyama
Journal: Nature Neuroscience (2023)

Abstract The meta-reinforcement learning (meta-RL) framework, which involves RL over multiple timescales, has been successful in training deep RL models that generalize to new environments. It has been hypothesized that the prefrontal cortex may mediate meta-RL in the brain, but the evidence is scarce. Here we show that the orbitofrontal cortex (OFC) mediates meta-RL. We trained mice and deep RL models on a probabilistic reversal learning task across sessions during which they improved their trial-by-trial RL policy through meta-learning. Ca 2+ /calmodulin-dependent protein kinase II-dependent synaptic plasticity in OFC was necessary for this meta-learning but not for the within-session trial-by-trial RL in experts. After meta-learning, OFC activity robustly encoded value signals, and OFC inactivation impaired the RL behaviors. Longitudinal tracking of OFC activity revealed that meta-learning gradually shapes population value coding to guide the ongoing behavioral policy. Our results indicate that two distinct RL algorithms with distinct neural mechanisms and timescales coexist in OFC to support adaptive decision-making.
Publisher Correction: Non-invasive temporal interference electrical stimulation of the human hippocampus
Authors: Ines R. Violante, Ketevan Alania, Antonino M. Cassarà, Esra Neufeld, Emma Acerbo, Romain Carron, Adam Williamson, Danielle L. Kurtin, Edward Rhodes, Adam Hampshire, Niels Kuster, Edward S. Boyden, Alvaro Pascual-Leone, Nir Grossman
Journal: Nature Neuroscience (2023)
The APOE-R136S mutation protects against APOE4-driven Tau pathology, neurodegeneration and neuroinflammation
Authors: Maxine R. Nelson, Peng Liu, Ayushi Agrawal, Oscar Yip, Jessica Blumenfeld, Michela Traglia, Min Joo Kim, Nicole Koutsodendris, Antara Rao, Brian Grone, Yanxia Hao, Seo Yeon Yoon, Qin Xu, Samuel De Leon, Tenzing Choenyi, Reuben Thomas, Francisco Lopera, Yakeel T. Quiroz, Joseph F. Arboleda-Velasquez, Eric M. Reiman, Robert W. Mahley, Yadong Huang
Journal: Nature Neuroscience (2023)

Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD), leading to earlier age of clinical onset and exacerbating pathologies. There is a critical need to identify protective targets. Recently, a rare APOE variant, APOE3-R136S (Christchurch), was found to protect against early-onset AD in a PSEN1-E280A carrier. In this study, we sought to determine if the R136S mutation also protects against APOE4-driven effects in LOAD. We generated tauopathy mouse and human iPSC-derived neuron models carrying human APOE4 with the homozygous or heterozygous R136S mutation. We found that the homozygous R136S mutation rescued APOE4-driven Tau pathology, neurodegeneration and neuroinflammation. The heterozygous R136S mutation partially protected against APOE4-driven neurodegeneration and neuroinflammation but not Tau pathology. Single-nucleus RNA sequencing revealed that the APOE4-R136S mutation increased disease-protective and diminished disease-associated cell populations in a gene dose-dependent manner. Thus, the APOE-R136S mutation protects against APOE4-driven AD pathologies, providing a target for therapeutic development against AD.
Senolytic therapy alleviates physiological human brain aging and COVID-19 neuropathology
Authors: Julio Aguado, Alberto A Amarilla, Atefeh Taherian Fard, Eduardo A Albornoz, Alexander Tyshkovskiy, Marius Schwabenland, Harman K Chaggar, Naphak Modhiran, Cecilia Gómez-Inclán, Ibrahim Javed, Alireza A Baradar, Benjamin Liang, Lianli Peng, Malindrie Dharmaratne, Giovanni Pietrogrande, Pranesh Padmanabhan, Morgan E Freney, Rhys Parry, Julian D J Sng, Ariel Isaacs, Alexander A Khromykh, Guillermo Valenzuela Nieto, Alejandro Rojas-Fernandez, Thomas P Davis, Marco Prinz, Bertram Bengsch, Vadim N Gladyshev, Trent M Woodruff, Jessica C Mar, Daniel Watterson, Ernst J Wolvetang
Journal: Nature Aging (2023)

Aging is a major risk factor for neurodegenerative diseases, and coronavirus disease 2019 (COVID-19) is linked to severe neurological manifestations. Senescent cells contribute to brain aging, but the impact of virus-induced senescence on neuropathologies is unknown. Here we show that senescent cells accumulate in aged human brain organoids and that senolytics reduce age-related inflammation and rejuvenate transcriptomic aging clocks. In postmortem brains of patients with severe COVID-19 we observed increased senescent cell accumulation compared with age-matched controls. Exposure of human brain organoids to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induced cellular senescence, and transcriptomic analysis revealed a unique SARS-CoV-2 inflammatory signature. Senolytic treatment of infected brain organoids blocked viral replication and prevented senescence in distinct neuronal populations. In human-ACE2-overexpressing mice, senolytics improved COVID-19 clinical outcomes, promoted dopaminergic neuron survival and alleviated viral and proinflammatory gene expression. Collectively our results demonstrate an important role for cellular senescence in driving brain aging and SARS-CoV-2-induced neuropathology, and a therapeutic benefit of senolytic treatments.
A drug-like molecule engages nuclear hormone receptor DAF-12/FXR to regulate mitophagy and extend lifespan
Authors: Manish Chamoli, Anand Rane, Anna Foulger, Shankar J Chinta, Azar Asadi Shahmirzadi, Caroline Kumsta, Dhanya K Nambiar, David Hall, Angelina Holcom, Suzanne Angeli, Minna Schmidt, Sharon Pitteri, Malene Hansen, Gordon J Lithgow, Julie K Andersen
Journal: Nature Aging (2023)
Refeeding-associated AMPKγ1 complex activity is a hallmark of health and longevity
Authors: Roberto Ripa, Eugen Ballhysa, Joachim D Steiner, Raymond Laboy, Andrea Annibal, Nadine Hochhard, Christian Latza, Luca Dolfi, Chiara Calabrese, Anna M Meyer, Maria Cristina Polidori, Roman-Ulrich Müller, Adam Antebi
Journal: Nature Aging (2023)

Late-life-initiated dietary interventions show limited efficacy in extending longevity or mitigating frailty, yet the underlying causes remain unclear. Here we studied the age-related fasting response of the short-lived killifish Nothobranchius furzeri. Transcriptomic analysis uncovered the existence of a fasting-like transcriptional program in the adipose tissue of old fish that overrides the feeding response, setting the tissue in persistent metabolic quiescence. The fasting-refeeding cycle triggers an inverse oscillatory expression of genes encoding the AMP-activated protein kinase (AMPK) regulatory subunits Prkag1 (γ1) and Prkag2 (γ2) in young individuals. Aging blunts such regulation, resulting in reduced Prkag1 expression. Transgenic fish with sustained AMPKγ1 countered the fasting-like transcriptional program, exhibiting a more youthful feeding and fasting response in older age, improved metabolic health and longevity. Accordingly, Prkag1 expression declines with age in human tissues and is associated with multimorbidity and multidimensional frailty risk. Thus, selective activation of AMPKγ1 prevents metabolic quiescence and preserves healthy aging in vertebrates, offering potential avenues for intervention.
Characteristics and long-term prognosis of Danish residents with a positive intrathecal antibody index test for herpes simplex virus or varicella-zoster virus compared with individuals with a positive cerebrospinal fluid PCR: a nationwide cohort study
Authors: Isabella L. Platz, Malte M. Tetens, Ram Dessau, Svend Ellermann-Eriksen, Nanna S. Andersen, Veronika Vorobieva Solholm Jensen, Christian Østergaard, Jacob Bodilsen, Kirstine Kobberøe Søgaard, Jette Bangsborg, Alex Christian Yde Nielsen, Jens Kjølseth Møller, Anne-Mette Lebech, Lars Haukali Omland, Niels Obel
Journal: Clinical Microbiology and Infection (2023)

ObjectivesWe compared characteristics and outcomes of individuals who in the cerebrospinal fluid (CSF) were positive for herpes simplex virus (HSV) or varicella-zoster virus (VZV)-intrathecal antibody index test ([AI]-positive) vs. individuals who were PCR-positive for HSV type 1 (HSV1), type 2 (HSV2), and for VZV.MethodsNationwide cohort study of all Danish residents with positive CSF-AI or -PCR for HSV or VZV (1995–2021). We calculated short- and long-term risks as age-, sex-, and comorbidity-adjusted odds ratios (aOR), adjusted hazard ratios (aHR), and absolute risk differences with 95% CIs.ResultsCompared with individuals with positive PCR for HSV1 (n = 321), HSV2 (n = 497), and VZV (n = 1054), individuals with a positive AI for HSV (n = 177) and VZV (n = 219) had CSF pleocytosis less frequently (leucocyte count >10/μL: HSV-AI: 39%, VZV-AI: 52%, HSV1-PCR: 81%, HSV2-PCR: 92%, VZV-PCR: 83%), and were less frequently diagnosed with central nervous system infection ([aOR {95%CI}]: HSV-AI vs. HSV1-PCR: [0.1 {0.1, 0.2}], HSV-AI vs. HSV2-PCR: [0.1 {0.0, 0.1}], VZV-AI vs. VZV-PCR: [0.2 {0.2, 0.3}]). Individuals with a positive HSV-AI or VZV-AI had increased risk of demyelinating disease ([aOR {95%CI}; aHR {95%CI}]: HSV-AI vs. HSV1-PCR: [4.6 {0.9, 24.5}; aHR not applicable], HSV-AI vs. HSV2-PCR: [10.4 {2.3, 45.9}; 12.4 {2.3, 66.0}], VZV-AI vs. VZV-PCR: [aOR not applicable; 10.3 {1.8, 58.8}]). Disability pension was less frequent among HSV-AI than HSV1-PCR cohort members (5-year risk difference: −23.6%, 95%CI: −35.2, −11.8), and more frequent among VZV-AI than VZV-PCR cohort members (5-year risk difference: 16.8%, 95%CI: 5.0, 28.7).DiscussionAI-positive individuals differ from PCR-positive individuals in several aspects. AI appears unspecific for current central nervous system infections.
PCSK7: A novel regulator of apolipoprotein B and a potential target against non-alcoholic fatty liver disease
Authors: Vatsal Sachan, Maïlys Le Dévéhat, Anna Roubtsova, Rachid Essalmani, Jean-Francois Laurendeau, Damien Garçon, Delia Susan-Resiga, Stéphanie Duval, Sahar Mikaeeli, Josée Hamelin, Alexandra Evagelidis, Michael Chong, Guillaume Paré, Elizabeta Chernetsova, Zu-Hua Gao, Isabelle Robillard, Matthieu Ruiz, Vincent Quoc-Huy Trinh, Jennifer L. Estall, May Faraj, Richard C. Austin, Martin Sauvageau, Annik Prat, Robert S. Kiss, Nabil G. Seidah
Journal: Metabolism (2023)
Learning Representations from Heart Sound: A Comparative Study on Shallow and Deep Models
Authors: Kun Qian, Zhihao Bao, Zhonghao Zhao, Tomoya Koike, Fengquan Dong, Maximilian Schmitt, Qunxi Dong, Jian Shen, Weipeng Jiang, Yajuan Jiang, Bo Dong, Zhenyu Dai, Bin Hu, Björn W Schuller, Yoshiharu Yamamoto
Journal: Cyborg and Bionic Systems (2023)

Leveraging the power of artificial intelligence to facilitate an automatic analysis and monitoring of heart sounds has increasingly attracted tremendous efforts in the past decade. Nevertheless, lacking on standard open-access database made it difficult to maintain a sustainable and comparable research before the first release of the PhysioNet CinC Challenge Dataset. However, inconsistent standards on data collection, annotation, and partition are still restraining a fair and efficient comparison between different works. To this line, we introduced and benchmarked a first version of the Heart Sounds Shenzhen (HSS) corpus. Motivated and inspired by the previous works based on HSS, we redefined the tasks and make a comprehensive investigation on shallow and deep models in this study. First, we segmented the heart sound recording into shorter recordings (10 s), which makes it more similar to the human auscultation case. Second, we redefined the classification tasks. Besides using the 3 class categories (normal, moderate, and mild/severe) adopted in HSS, we added a binary classification task in this study, i.e., normal and abnormal. In this work, we provided detailed benchmarks based on both the classic machine learning and the state-of-the-art deep learning technologies, which are reproducible by using open-source toolkits. Last but not least, we analyzed the feature contributions of best performance achieved by the benchmark to make the results more convincing and interpretable.
An umbrella review of the benefits and risks associated with youths’ interactions with electronic screens
Authors: Taren Sanders, Michael Noetel, Philip Parker, Borja Del Pozo Cruz, Stuart Biddle, Rimante Ronto, Ryan Hulteen, Rhiannon Parker, George Thomas, Katrien De Cocker, Jo Salmon, Kylie Hesketh, Nicole Weeks, Hugh Arnott, Emma Devine, Roberta Vasconcellos, Rebecca Pagano, Jamie Sherson, James Conigrave, Chris Lonsdale
Journal: Nature Human Behaviour (2023)
Research Priorities for Pediatric Emergency Care to Address Disparities by Race, Ethnicity, and Language
Authors: Elyse N. Portillo, Chris A. Rees, Emily A. Hartford, Zachary C. Foughty, Michelle L. Pickett, Colleen K. Gutman, Bashar S. Shihabuddin, Eric W. Fleegler, Corrie E. Chumpitazi, Tiffani J. Johnson, David Schnadower, Kathy N. Shaw
Journal: JAMA Network Open (2023)

Importance Health care disparities are well-documented among children based on race, ethnicity, and language for care. An agenda that outlines research priorities for disparities in pediatric emergency care (PEC) is lacking. Objective To investigate research priorities for disparities in PEC among medical personnel, researchers, and health care–affiliated community organizations. Design, Setting, and Participants In this survey study, a modified Delphi approach was used to investigate research priorities for disparities in PEC. An initial list of research priorities was developed by a group of experienced PEC investigators in 2021. Partners iteratively assessed the list through 2 rounds of electronic surveys using Likert-type responses in late 2021 and early 2022. Priorities were defined as achieving consensus if they received a score of highest priority or priority by at least 60% of respondents. Asynchronous engagement of participants via online web-conferencing platforms and email correspondence with electronic survey administration was used. Partners were individuals and groups involved in PEC. Participants represented interest groups, research and medical personnel organizations, health care partners, and laypersons with roles in community and family hospital advisory councils. Participants were largely from the US, with input from international PEC research networks. Outcome Consensus agenda of research priorities to identify and address health care disparities in PEC. Results PEC investigators generated an initial list of 27 potential priorities. Surveys were completed by 38 of 47 partners (80.6%) and 30 of 38 partners (81.1%) in rounds 1 and 2, respectively. Among 30 respondents who completed both rounds, there were 7 family or community partners and 23 medical or research partners, including 4 international PEC research networks. A total of 12 research priorities achieved the predetermined consensus threshold: (1) systematic efforts to reduce disparities; (2) race, ethnicity, and language data collection and reporting; (3) recognizing and mitigating clinician implicit bias; (4) mental health disparities; (5) social determinants of health; (6) language and literacy; (7) acute pain–management disparities; (8) quality of care equity metrics; (9) shared decision-making; (10) patient experience; (11) triage and acuity score assignment; and (12) inclusive research participation. Conclusions and Relevance These results suggest a research priority agenda that may be used as a guide for investigators, research networks, organizations, and funding agencies to engage in and support high-priority disparities research topics in PEC.
Molecular biomarkers for vascular cognitive impairment and dementia
Authors: Satoshi Hosoki, Gurpreet K. Hansra, Tharusha Jayasena, Anne Poljak, Karen A. Mather, Vibeke S. Catts, Ruslan Rust, Abhay Sagare, Jason C. Kovacic, Amy Brodtmann, Anders Wallin, Berislav V. Zlokovic, Masafumi Ihara, Perminder S. Sachdev
Journal: Nature Reviews Neurology (2023)
Risk of Suicidal Ideation and Behavior in Individuals With Parkinson Disease
Authors: Aaron Shengting Mai, Yinxia Chao, Bin Xiao, Zhidong Zhou, Jung Hahn Yong, Ainsley Ryan Yan Bin Lee, Eng-King Tan
Journal: JAMA Neurology (2023)

Suicide risk may be increased in patients with Parkinson disease (PD), a common neurodegenerative condition. Mood disorders, especially depression, are prevalent in patients with PD who report suicidality.
Prioritizing the Exposome to Reduce Cardiovascular Disease Burden
Authors: Erica S. Spatz, Kai Chen, Harlan M. Krumholz
Journal: JAMA Cardiology (2023)

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Widening Gender Gap in Life Expectancy in the US, 2010-2021
Authors: Brandon W. Yan, Elizabeth Arias, Alan C. Geller, Donald R. Miller, Kenneth D. Kochanek, Howard K. Koh
Journal: JAMA Internal Medicine (2023)

This cross-sectional study systematically examines the contributions of COVID-19 and other underlying causes of death to the widened gender life expectancy gap from 2010 to 2021.